This invention relates generally to the field of pyridine chemistry, and in particular to direct and substituted amination reactions of 3-alkylpyridines and to an improved process for synthesizing the 2-alkylamino-5-alkylpyridine and 2-amino-5-alkylpyridine products of such reactions.
In 1914, Chichibabin and Seide first reported that .alpha.-picoline, or more commonly 2-methypyridine, underwent direct amination in the free .alpha.-position on the ring when treated with sodium amide in toluene at elevated temperatures. Chichibabin and Seide, J. Russ. Phys. Chem. Soc., 46 1216 (1914). This reaction was later extended by Chichibabin and his contemporaries to amination of many pyridine, quinoline and isoquinoline bases. It has since been recognized as one of the more important and influential developments in pyridine chemistry, so much so that the reaction itself has become synonymous with the name of its principal discoverer. Its commercial importance should also not be discounted as, for example, the 2-amino amination product of pyridine itself has become an enormously important and useful starting material for further synthesis in many areas.
The first attempt known to applicants to prepare a substituted aminopyridine during amination was reported by these same authors, Chichibabin and Seide, in the same 1914 paper, as the treatment of pyridine with the sodium salt of aniline reportedly gave 2-anilinopyridine in a very small yield. Substituted Chichibabin aminations have since been extended to a limited degree as, for example, by Bergstrom et al. who reported preparing 2-methylaminopyridine, 2-butylaminopyridine, 2-cyclohexylaminopyridine, 2-n-heptylaminopyridine, 2-methylaminoquinoline, 2-butylaminoquinoline and 2-cyclohexylaminoquinoline in yields ranging from 21-73% by heating the eutectic mixture of sodamide and potassium amide with the heterocycle dissolved in the corresponding primary aliphatic amine. Bergstrom, Sturz, and Tracey, J. Org. Chem., 11, 239 (1946). Abramovitch and Rogers reported that treatment of 3-picoline-1-oxide with N-phenylbenzimidoyl chloride gave predominently 2-(N-benzoylanilino)-5-methylpyridine which can be converted to 2-anilino-5-methylpyridine by hydrolysis. Abramovitch and Rogers, J. Org. Chem., 39, 1802 (1974).
Most prolific in the area of substituted Chichibabin aminations have been Kovacs and Vajda, who in a series of papers reported preparing 2-butylaminopyridine, 2-butylaminoquinoline, 2-dodecylaminopyridine, 2-cyclohexylaminopyridine, 2-benzylaminopyridine, 2-dimethylaminoethylamino-6methylpyridine, 2-dimethylaminoethylaminopyridine 2-dimethylaminoethylaminoquinoline and 2-diethylaminoethylaminopyridine in yields ranging from 11-79% by replacing the amide eutectic mixture used by Bergstrom et al. with powdered sodium or potassium. In particular, their reported success in directly substituting an alkylamine at the 2-position of the pyridine ring involved heating pyridine, alpha-picoline or quinoline with the corresponding anhydrous primary alkylamine or aralkylamine in boiling toluene in the presence of powdered sodium or potassium. Kovacs and Vajda, Acta Chim. Acad. Sci. Hung., 21, 445 (1959), C.A. 55, 1608b (1961); Kovacs and Vajda, Chem. Ind., 259 (1959); Kovacs and Vajda, Acta. Chim. Acad. Sci. Hung., 29, 245 (1961), C. A. 57, 5892h (1962); Kovacs and Vajda, Acta Pharm. Hung., 31, Suppl. 72 (1961), C.A. 56, 5922e (1962).
Importantly, Kovacs and Vajda reported no reaction when only the alkylamine was heated with powdered sodium in toluene in an attempted preliminary reaction. This indicated no formation of the sodium alkylamide. They also reported low yields of the sodium salt even after long reaction times when sodamide was substituted for powdered sodium in the same reaction. They concluded that the condition for a successful substituted amination reaction required that the base and the amine react simultaneously with the powdered sodium. Vajda and Kovacs, Rec. Trav. Chim., 80, 47 (1961). Moreover, under these conditions considerable amounts of dipyridyls and tarry materials are also formed because of competing reactions of sodium with the heterocyclic compound. Other efforts to prepare sodium salts of alkylamines have reported similar marginal to poor success, or in the case of one author, required a stable sodium dispersion at very low temperatures using hazardous liquid butadiene. DePree, U.S. Pat. No. 2,799,705 (1957). Without any efficient, practicable method for preparing these salts, the accepted practice at this time for substituting a heterocyclic base during a substituted Chichibabin amination remains the Kovacs and Vajda procedure of reacting the base and the amine simultaneously with powdered sodium or potassium.
Referring specifically to 3-substituted pyridines, applicants are unaware of any prior attempted substituted Chichibabin aminations of these compounds . . . successful or not. It is known that an appreciable number of these bases, and particularly the 3-alkyl derivatives, undergo simple amination with sodamide to produce predominantly a 2-amino-3-alkylpyridine reaction product ("2,3-isomer"), and to a much lesser extent a 2-amino-5-alkylpyridine ("2,5-isomer"). For example, the Chichibabin amination of 3-methylpyridine, also known as 3- or beta-picoline, with sodamide has been reported to yield these 2,3- and 2,5-isomers in a ratio of 10.5:1. Abramovitch, Advan. Heterocycl. Chem., 6, 294 (1966). This is extremely unfortunate as the 2,5-isomers are much preferred because of their usefulness as starting materials and intermediates for the preparation of herbicides, insecticides and pharmaceuticals. The 2,3-isomers are comparatively of little or no use at this time, and their high yields significantly add to the expense of the process both in starting material consumed and in disposal of the 2,3 -isomers. A way to improve the yield of these 2,5-isomer amination products, and of 2-amino-5-methylpyridine as being commercially most important at this time, is greatly needed.